This proposal is for an ancillary study to and approved by the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) in response to PAR-09-247. The broad, long-term objective is to improve the health of persons with Non-Alcoholic Fatty Liver Disease (NAFLD). The immediate objective is to overcome a key barrier in the diagnosis and monitoring of NAFLD: the lack of accurate and precise non-invasive biomarkers to grade necroinflammatory activity, stage fibrosis, and differentiate NASH - the more rapidly progressive variant of NAFLD, and target for therapeutic intervention - from isolated steatosis. Health relatedness: NAFLD is the most common chronic liver disease in children and adults in the United States, and it is intimately related to insulin resistance and obesity. NAFLD may progress to cirrhosis and liver cancer, and it contributes to the development of diabetes and cardiovascular disease. Currently, accurate assessment of NAFLD requires liver biopsy, a requirement that hampers clinical care and impedes NAFLD research. This proposal will develop much-needed non-invasive MR-based biomarker panels to grade and stage NAFLD. The integration of these biomarker panels into clinical practice and clinical trial endpoints will advance NAFLD care and research. The specific aims are to develop panels of MR-based biomarkers in children and adults with NAFLD to grade hepatic necroinflammatory activity (Aim 1), stage fibrosis (Aim 2), and differentiate NASH from isolated steatosis (Aim 3). The reference standard will be liver histology. Design: We propose a six-site prospective, observational, cross-sectional ancillary study to the NASH CRN, the leading NAFLD research network in the United States. The NASH CRN will provide a large, ethnically diverse population of clinically and histologically characterized subjects. Methods: 200 pediatric and 200 adult NASH CRN research subjects undergoing liver biopsy will be enrolled and have research MR examinations within 90 days of their biopsy. MR examinations will include advanced MR imaging, MR spectroscopy, and MR elastography techniques and last one hour without contrast agent use. Techniques will be optimized to mitigate confounding effects. Candidate MR- based biomarkers will be measured including fat fraction, viscoelasticity parameters, apparent diffusion coefficient, true diffusion coefficient, pseudo-diffusion coefficient, perfusion fraction, and extrahepatic adipose tissue volumes. Statistical analyses: MR measurements will be compared with histology findings. Multivariable models will be built to develop MR-based biomarker panels to grade hepatic necroinflammatory activity, stage fibrosis and differentiate NASH from isolated steatosis. For each aim, panels will be developed separately in children and adults. The development of accurate, precise non-invasive MR-based biomarker panels to grade and stage NAFLD will advance clinical care and research in this disease. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease is the most common chronic liver disease in children and adults in the United States, is present in as many as 80 million Americans, and can progress to cirrhosis and liver cancer. Currently, liver biopsy is the only way to reliably evaluate the liver in persons with this disease. This proposal will develop new, safe, non-invasive, accurate methods to evaluate the liver in affected children and adults using magnetic resonance imaging.